Alterations of epigenetic regulation are a characteristic of many diseases. The myocyte enhancer factor 2 (MEF2) transcription factor plays central roles in the transmission of extracellular signals to the genome and in the activation of the genetic programs that control cell differentiation, proliferation, morphogenesis, survival and apoptosis of a wide range of cell types (Potthoff et al., 2007). The spectrum of genes activated by MEF2 in different cell types depends on extracellular signaling and on cofactor interactions that modulate MEF2 activity. To drive the expression of MEF2 target genes, MEF2 relies on the recruitment of and cooperation with a number of transcription factors including, but not limited to, calcineurin binding protein 1, E1A binding protein P300, CREB binding protein, extracellular signal-regulated kinase 5, myoblast differentiation protein, Smad protein, nuclear factor of activated T cell, myocardin, and positive transcription elongation factor b.
Histone deacetylases (HDACs) are a major class of epigenetic regulators of diverse cellular processes. This family of enzymes can be phylogenetically divided into four classes: class I (HDAC1, 2, 3 and 8), class II (HDAC4, 5, 7, 9, 6 and 10) and class IV (HDAC 11), while class III (sirtuins, Sirt1-Sirt7) represents a structurally and functionally distinct family of HDAC enzymes. Class II HDACs can be further divided into class IIa (HDAC 4, 5, 7, and 9) and class IIb (HDAC 6 and 10). Recent studies show that MEF2 forms an intimate partnership with class IIa histone deacetylases (HDACx), which together function as a point of convergence of multiple epigenetic regulatory mechanisms.
Class IIa HDACs contain a unique regulatory domain, which is N-terminal to the catalytic domain and absent in other HDAC members. This regulatory HDAC domain mediates interactions with the Myocyte Enhancer Factor-2 (MEF2A-D) transcription factor proteins. Class IIa HDACs do not bind to DNA but depend on their interaction with the sequence-specific transcription factor MEF2 for genomic targeting (Wang et al., 2001; Han et al., 2005). This interaction is mediated by a short amphipathic helix conserved in the N-terminal regulatory domain of class IIa HDACs. Crystallography analyses and in vitro biochemical studies reveal that the amphipathic helix binds to a highly conserved hydrophobic groove on the MADS-box/MEF2 domain of MEF2 (Han et al., 2005; Han et al., 2003).